How can a point mutation in an ion channel cause motor deficits, mental retardation and massive neurodegeneration? It was recently discovered that mutations in potassium channel Kv3.3 is the cause of human spinocerebellar ataxia SCA13. Affected individuals with mutations in Kv3.3 display cerebellar atrophy and present with severe neuromuscular and cognitive symptoms. This research focuses on the function of Kv3.3 channels in Purkinje cells of the cerebellum, and is a contribution in understanding the pathophysiology of disease in humans with SCA13. Kv3.3 is most strongly expressed in Purkinje cells, with protein localization in somas, axons and dendrites. A highly stereotyped response of Purkinje cells is the complex spike, a massive all-or-none response to climbing fiber activation involving somatic and dendritic electrical activity and large dendritic Ca ++ transients. Due to the expression and electrical properties of Kv3.3 subunits, we hypothesize that they are active in the complex spike and important in the regulation dendritic Ca++ influx. We intend to use pharmacological and genetic approaches to elucidate the specific functions of somatic and dendritic Kv3.3 channels in modulating the electrical properties and Ca++ dynamics of Purkinje cells. Altered Ca++ homeostasis is a probable cause of pathology in humans with Kv3.3 mutations, and these studies are critical in establishing the roles of these channels in regulating Ca++ dynamics. Studies in our laboratory demonstrated the modulation of Kv3.3 subunits by PKC in heterologous expression systems. PKC plays very important roles in Purkinje cell function and plasticity, and it is possible that this modulation of Kv3.3 is an important mechanism in the cellular effects of PKC. Moreover, mutations in PKC gamma are the cause of human spinocerebellar ataxia SCA14. Thus, mutations in either Kv3.3 or PKC gamma produce similar phenotypes, posing the intriguing possibility that modulation of Kv3.3 channels is involved in the expression of disease in humans with mutations in PKC gamma. A second aim of this study is to demonstrate the modulation and Kv3.3 subunits in Purkinje cells and begin to explore the implications of this modulation on Purkinje cell physiology. [unreadable] [unreadable] [unreadable]